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1.  Regional differences regarding risk of developing Rheumatoid Arthritis in Stockholm County, Sweden 
Scandinavian journal of rheumatology  2013;42(5):10.3109/03009742.2013.769062.
Rheumatoid arthritis (RA) is a complex disease that is associated with genetic and environmental factors. We have investigated geospatial variation in risk of developing RA within Stockholm County, with respect to established environmental risk factors for RA, as well as serologically-defined subgroups of RA.
Information regarding geographical location for 1432 cases and 2529 controls from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, living in Stockholm County at RA symptom onset, or matched date for controls, was used to estimate geospatial variation in risk. We used Generalized Additive Models (GAM) to create a risk surface, calculate odds ratios and adjust for potential confounding by smoking, educational level and RA within family. We performed a stratified analysis based on presence/absence of antibodies to citrullinated peptides (ACPA).
We found significant spatial variation in the odds of developing RA in Stockholm County. After adjustment for smoking, educational level and family history of RA, this geospatial variation remained. The stratified analysis showed areas with higher odds ratios for ACPA-positive RA and ACPA-negative RA, after adjusting for smoking, educational level and having a family history of RA. Living in the city of Stockholm was associated with decreased risk of RA.
The risk of developing RA in Stockholm County is not evenly distributed and there are areas of increased risk that could not be explained by known factors. Further investigations of local exposures or social factors are warranted.
PMCID: PMC3815679  PMID: 23611369
Rheumatoid Arthritis; Epidemiologic methods; Antibodies; Geography; Risk; Smoking; ACPA; Stockholm
2.  The management of rheumatic diseases in pregnancy 
Pregnancy can create a challenge for physicians caring for women with rheumatic diseases. For many women with rheumatoid arthritis (RA), pregnancy can provide a reprieve from long-term joint pain and inflammation, but others will not experience remission and will continue to need medication. Systemic lupus erythematosus (SLE) may remain quiet in some women, but in others may become more aggressive during pregnancy, putting both mother and foetus at risk. Women with limited scleroderma can do remarkably well, but scleroderma renal crises can be difficult to manage. A third of pregnancies in women with antiphospholipid syndrome (APS) may be refractory to our best therapy. In general, active inflammation from rheumatic diseases poses a stronger threat to the well-being of both mother and foetus than many immunosuppressant medications. Therefore, continued immunosuppression with the least risky medications will allow for the most optimal pregnancy outcomes.
PMCID: PMC3724464  PMID: 20337545
3.  MALDI MS imaging as a powerful tool for investigating synovial tissue 
To identify and image protein biomarker candidates in the synovial tissue of patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA).
A novel matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) technique was applied to the analysis of synovial tissue. Patients were classified according to the American College of Rheumatology (ACR) criteria for RA. Frozen sections were stained to obtain morphological data. Serial sections were desiccated, and spotted with matrix for MALDI analysis. Ions generated by laser irradiation of the tissue were separated in time, based on their m/z ratio, and were subsequently detected. IMS was used in a ‘profiling’ mode to detect discrete spots for rapid evaluation of proteomic patterns in various tissue compartments. Photomicrographs of the stained tissue images were reviewed by a pathologist. Areas of interest (10 discrete areas/compartment) were marked digitally and the histology-annotated images were merged to form a photomicrograph of the section taken before the MALDI measurement. Pixel coordinates of these areas were transferred to a robotic spotter, the matrix was spotted, and the coordinates of the spots were transferred to a mass spectrometer for spectral acquisition. The data generated were then subjected to biocomputation analysis to reveal the biomarker candidates.
Several peaks (m/z) consistent in mass with calgranulins, defensins, and thymosins were detected and their distribution in various synovial compartments (synovial lining and sublining layer) was demonstrated.
MALDI IMS is a powerful tool for the rapid detection of numerous proteins (in situ proteomics) and was applied here for the analysis of the distribution of proteins in synovial tissue sections.
PMCID: PMC3514013  PMID: 22639849
4.  The impact of self-reported arthritis and diabetes on response to a home-based physical activity counseling intervention 
Physical activity (PA) has potential to improve outcomes in both arthritis and diabetes, but these conditions are rarely examined together. Our objective was to explore whether persons with arthritis alone or those with both arthritis and diabetes could improve amounts of PA with a home-based counseling intervention.
As part of the Veterans LIFE Study, veterans ages 70–92 were randomized to usual care or a twelve month PA counseling program. Arthritis and diabetes were assessed via self-report. Mixed models were used to compare trajectories for minutes of endurance and strength training PA for persons with no arthritis (n=85), arthritis (n=178), and arthritis plus diabetes (n=84).
Recipients of PA counseling increased minutes of PA per week independent of disease status (treatment arm by time interaction P<0.05 for both; endurance training time P=0.0006 and strength training time P<0.0001). Although PA was lower at each wave among persons with arthritis, and even more so among persons with arthritis plus diabetes, the presence of these conditions did not significantly influence response to the intervention (Arthritis/Diabetes group X time interactions P>0.05 for both outcomes) as each group experienced a nearly two-fold or more increase in PA.
A home-based PA intervention was effective in increasing minutes of weekly moderate intensity endurance and strength training PA in older veterans, even among those with arthritis or arthritis plus diabetes. This program may serve as a useful model to improve outcomes in older persons with these pervasive diseases.
PMCID: PMC2963864  PMID: 20429674
Physical Activity; Arthritis; Diabetes; Counseling
5.  Does Diabetes Associate with Poorer Self-Efficacy and Motivation for Physical Activity in Older Adults with Arthritis? 
To explore 1) Whether arthritis associates with poorer self-efficacy and motivation for, and participation in, two specific types of physical activity (PA): Endurance training (ET) and strength training (ST), and 2) If the added burden of diabetes contributes to a further reduction in these PA determinants and types.
Self-efficacy and motivation for exercise and minutes per week of ET and ST were measured in 347 older Veterans enrolled in a home-based PA counseling intervention. Regression analyses were used to compare high versus low self-efficacy and motivation and PA minutes in persons without arthritis, with arthritis alone, and with arthritis plus diabetes.
Persons with arthritis alone reported lower self-efficacy for ET and ST than those without arthritis (Odds ratio[OR]ET 0.71 (0.39,1.20); ORST 0.69 (0.39,1.20)). A further reduction in self-efficacy for these two types of PA was observed for those with both arthritis and diabetes (ORET 0.65 (0.44,0.92); ORST 0.64 (0.44,0.93); trend P<0.001). There was no trend towards a reduction in motivation for PA in those with arthritis alone or arthritis and diabetes. Persons with arthritis exhibited higher motivation for ET than those without arthritis (ORET 1.85 (1.12,3.33). There were no significant differences between the three groups in minutes of ET (P=0.93), but persons with arthritis plus diabetes reported significantly less ST compared to individuals with arthritis only (P=0.03).
Despite reduced self-efficacy for ET and ST and less ST in older persons with arthritis, motivation for both PA types remains high, even in the presence of diabetes.
PMCID: PMC3058748  PMID: 20604671
exercise self-efficacy; co-morbidity; strength training
6.  S100A9 is not essential for disease expression in an acute (K/BxN) or chronic (CIA) model of inflammatory arthritis 
S100A8 (calgranulin A, MRP8) and S100A9 (calgranulin B, MRP14) are calcium-binding proteins highly expressed by activated myeloid cells and thought to be involved in the pathogenesis of inflammatory diseases. Circulating levels of S100A8/S100A9 are elevated in both human and experimental models of autoimmune disease, including rheumatoid arthritis (RA).
Mice deficient in S100A9 (S100A9−/−) and wild-type controls were immunized using standard techniques for the K/BxN serum transfer or the collagen-induced arthritis (CIA) model.
S100A9−/− animals, with defective expression of both S100A8 and S100A9 proteins, had similar arthritis and histopathology to that of wild-type controls in both mouse models.
S100A8 and S100A9 are not essential for disease expression in either the K/BxN serum transfer or the CIA model of inflammatory arthritis.
PMCID: PMC2866179  PMID: 19922019
7.  Lack of association between beta 2-adrenergic receptor polymorphisms and Juvenile Idiopathic Arthritis 
Juvenile idiopathic arthritis (JIA) is a chronic autoimmune arthropathy. β-2 adrenergic receptors are a link between the sympathetic nervous system and the immune system. Associations between variants in the gene encoding the β2-adrenergic receptor (ADRB2) and autoimmune disorders such as rheumatoid arthritis (RA) have been demonstrated. We aimed to investigate ADRB2 variants for association with JIA.
Genotypes and haplotypes of two ADRB2 variants (G16R and Q27E) were determined in 348 children with JIA and 448 healthy controls, by direct molecular haplotyping using melting-curve analysis of a fluorescently labeled loci-spanning probe. Case-control analysis was performed to investigate whether ADRB2 variants were associated with JIA.
No association was found between JIA and alleles, genotypes or haplotypes of ADRB2. Specifically the haplotype that demonstrated a strong association with RA (R16/Q27) was not associated with JIA. None of the variants demonstrated association after stratification by JIA subtypes or gender.
Our results indicate that ADRB2 variants are not associated with JIA or any of the major JIA subtypes. These observations suggest that although they share several clinical and pathological features, JIA and RA have unique genetic associations.
PMCID: PMC2838190  PMID: 19177262
JIA; association; beta adrenergic receptor; genetic; polymorphism; molecular haplotyping
8.  Gene expression analysis of rheumatoid arthritis synovial lining regions by cDNA microarray combined with laser microdissection: up-regulation of inflammation-associated STAT1, IRF1, CXCL9, CXCL10, and CCL5 
The main histological change in rheumatoid arthritis (RA) is the villous proliferation of synovial lining cells, an important source of cytokines and chemokines, which are associated with inflammation. The aim of this study was to evaluate gene expression in the microdissected synovial lining cells of RA patients, using those of osteoarthritis (OA) patients as the control.
Samples were obtained during total joint replacement from 11 RA and five OA patients. Total RNA from the synovial lining cells was derived from selected specimens by laser microdissection (LMD) for subsequent cDNA microarray analysis. In addition, the expression of significant genes was confirmed immunohistochemically.
The 14 519 genes detected by cDNA microarray were used to compare gene expression levels in synovial lining cells from RA with those from OA patients. Cluster analysis indicated that RA cells, including low- and high-expression subgroups, and OA cells were stored in two main clusters. The molecular activity of RA was statistically consistent with its clinical and histological activity. Expression levels of signal transducer and activator of transcription 1 (STAT1), interferon regulatory factor 1 (IRF1), and the chemokines CXCL9, CXCL10, and CCL5 were statistically significantly higher in the synovium of RA than in that of OA. Immunohistochemically, the lining synovium of RA, but not that of OA, clearly expressed STAT1, IRF1, and chemokines, as was seen in microarray analysis combined with LMD.
Our findings indicate an important role for lining synovial cells in the inflammatory and proliferative processes of RA. Further understanding of the local signalling in structural components is important in rheumatology.
PMCID: PMC3400100  PMID: 22401175
9.  Short-term treatment with a gonadotropin-releasing hormone antagonist, cetrorelix, in rheumatoid arthritis (AGRA): a randomized, double-blind, placebo-controlled study 
Gonadotropin-releasing hormone (GnRH) stimulates immune responses; therefore, antagonizing GnRH with cetrorelix may have anti-inflammatory effects. The aim of this study was to assess short-term cetrorelix therapy in rheumatoid arthritis (RA) patients.
In this proof-of-concept, randomized, double-blind study involving 99 patients with active, long-standing RA, 48 patients received subcutaneous cetrorelix (5 mg/day on days 1 and 2; 3 mg/day on days 3–5) and 51 received placebo. The primary end-point was the change in the 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) by day 5, when the greatest GnRH suppression was anticipated. Secondary end-points included the change in tumour necrosis factor (TNF)-α, and achievement of American College of Rheumatology (ACR) responses and DAS28-CRP < 2.6 by day 5. Patients were followed up on days 10 and 15.
By day 5, DAS28-CRP was non-significantly reduced by 0.82 in the cetrorelix group compared to a 0.57 reduction in the placebo group (p = 0.091), TNF-α (log pg/mL) was significantly reduced in the cetrorelix group compared with the placebo group [0.55, 95% confidence interval (CI) 0.08–1.01, p = 0.023], and more patients on cetrorelix achieved ACR20 responses (40% vs. 18%, p = 0.015) and DAS28-CRP < 2.6 (13% vs. 0%, p = 0.009). Inflammatory markers increased towards baseline levels after withdrawal of treatment. Rates of adverse events were similar in both groups.
Although there was no significant difference in the primary end-point between groups, antagonizing GnRH led to significant improvements in key secondary end-points. Thus, GnRH antagonists may have rapid anti-inflammatory effects in RA, already occurring within 5 days. The data suggest a novel mode of action for TNF-α inhibition in RA, and potentially in other autoimmune diseases.
PMCID: PMC3913106  PMID: 24182325

Results 1-10 (10)